A novel common variant in DCST2 is associated with length in early life and height in adulthood

Research output: Contribution to journalJournal articleResearchpeer-review

  • Ralf J P van der Valk
  • Eskil Kreiner-Møller
  • Marjolein N Kooijman
  • Mònica Guxens
  • Evangelia Stergiakouli
  • Annika Sääf
  • Jonathan P Bradfield
  • Frank Geller
  • M Geoffrey Hayes
  • Diana L Cousminer
  • Antje Körner
  • Elisabeth Thiering
  • John A Curtin
  • Ronny Myhre
  • Ville Huikari
  • Raimo Joro
  • Marjan Kerkhof
  • Nicole M Warrington
  • Niina Pitkänen
  • Ioanna Ntalla
  • Momoko Horikoshi
  • Riitta Veijola
  • Rachel M Freathy
  • Yik-Ying Teo
  • Sheila J Barton
  • David M Evans
  • John P Kemp
  • Beate St Pourcain
  • Susan M Ring
  • George Davey Smith
  • Anna Bergström
  • Inger Kull
  • Hakon Hakonarson
  • Frank D Mentch
  • Hans Bisgaard
  • Chawes, Bo Lund Krogsgaard
  • Stokholm, Jakob
  • Johannes Waage
  • Patrick Eriksen
  • Astrid Sevelsted
  • Mads Melbye
  • Cornelia M van Duijn
  • Carolina Medina-Gomez
  • Albert Hofman
  • Johan C de Jongste
  • H Rob Taal
  • André G Uitterlinden
  • Loren L Armstrong
  • Pers, Tune H
  • Bønnelykke, Klaus
  • Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

Original languageEnglish
JournalHuman Molecular Genetics
Volume24
Issue number4
Pages (from-to)1155-68
Number of pages14
ISSN0964-6906
DOIs
Publication statusPublished - 15 Feb 2015

    Research areas

  • Adaptor Proteins, Signal Transducing, Adult, Age Factors, Alleles, Body Height, Computational Biology, Databases, Genetic, Genetic Association Studies, Genetic Variation, Genotype, Humans, Infant, Newborn, Membrane Proteins, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Reproducibility of Results

ID: 154222301